Synthesis of 4,5-diarylquinazolines: A system with cofacial aromatic rings. Diazines. Part 39

Article abstract of DOI:10.1016/j.tet.2004.04.065

Using metallation reactions and Pd-catalyzed coupling, we report here two synthetic routes leading to eight new 4,5-di(hetero)arylquinazolines. Non-linear activity has been highlighted for some of these compounds with stacked aromatic rings.

Full text of DOI:10.1016/j.tet.2004.04.065

Tetrahedron 60 (2004) 5373–5382
Synthesis of 4,5-diarylquinazolines: a system with cofacial
aromatic rings. Diazines. Part 39
*
´
´
´ ˆ
Alexandrine Busch, Valerie Gautheron Chapoulaud, Jerome Audoux, Nelly Ple and Alain Turck
´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, IRCOF-INSA, B.P. 08, 76131 Mont Saint Aignan Cedex, France
Received 24 February 2004; revised 21 April 2004; accepted 22 April 2004
Abstract—Using metallation reactions and Pd-catalyzed coupling, we report here two synthetic routes leading to eight new 4,5-di(hetero)-
arylquinazolines. Non-linear activity has been highlighted for some of these compounds with stacked aromatic rings.
q 2004 Published by Elsevier Ltd.
Stacked or cofacial aromatic or heteroaromatic rings appear
in a number of natural products, the most important being
nucleic acids where the rings are offset to each other.1
Furthermore, several studies dealing with 1,8-diaryl2–10 and
1,8-dihetarylnaphthalenes,11–13 where the aromatic rings
are p-stacked, have been developed. In such naphthalenes,
the two aromatic rings are held cofacial but are splayed out
from each other and are able to rotate about the bonds
attaching them to the rigid naphthalene frame. Crystal
structures show that the aryl rings in such naphthalenes are
not parallel to each other but are tilted away in order to
increase separation and thereby minimize electrostatic
repulsion.
benzodiazines using metallation and cross-coupling reac-
tions, we report here the synthesis of various di(hetero)aryl-
quinazolines I–III (Scheme 1).
In these structures, one aryl substituent is rendered electron-
rich by an electron-donor (D) or an heteroarene while the
other has reduced density as a result of an electron-
withdrawing group (A) or heteroarene, it could also be
noticed that position of aryl or hereroarene at the C4 and C5
positions avoid a direct conjugation between the donor (D)
and acceptor (A). So compounds of this type offer potential
non-covalent interactions between the opposite faces of the
D/A p-electron systems.15 To improve this through-space
effect which is defined as Coulombic (electrostatic)
interactions, we have synthesized compounds with The
(A) p-electron system on the pyrimidine moiety which is a
p-deficient ring and the (D) p-electron system on the
benzene ring.
Among the 1,8-di(hetero)arylnaphthalenes previously
described in the literature, some of them have highlighted
interesting non-linear optic (NLO) activities.14 These results
urged us to synthesize aza-analogues of such structures
which could present potential applications in NLOs.
Using cross-coupling reactions and metallations, we report
here two synthetic routes for compounds of type I–III
(Scheme 1), the first one involves cyclization of substituted
benzene derivatives to obtain 4(3H)-quinazolinone deriva-
tives, whereas the second one uses in a first step metallation
reaction of 4(3H)-quinazolinone to functionalize the
benzene moiety.
In the context of our studies on the synthesis of
In the first synthetic route, the starting material was the
methyl 2-amino-6-methoxybenzoate 1 prepared according
to the procedure previously described in the literature.16
Reaction of 1 with formamidine acetate at 180 8C led to
5-methoxy-4-(3H)-quinazolinone 2 which has been con-
verted with a mixture of phosphorus pentachloride and
phosphorus oxychloride to 4-chloro-5-methoxy-4-(3H)-
quinazolinone 3. This last compound underwent cross-
coupling reactions under Suzuki or Stille conditions
allowing formation of the first aryl–aryl bond at the C4
position (Scheme 2).
Scheme 1.
Keywords: Metallation; Cross-coupling reactions; 4,5-Di(hetero)-
arylquinazolines; Non-linear optics.
*
Corresponding author. Tel.: þ33-2-35-52-29-02; fax: þ33-2-35-52-29-
62; e-mail address: nelly.ple@insa-rouen.fr
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.04.065

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A. Busch et al. / Tetrahedron 60 (2004) 5373–5382
Scheme 2.
In a second time, cleavage of the methoxy group has been
achieved with pyridinium hydrochloride under reflux
leading to corresponding hydroxy compounds 7–9 which
were reacted with trifluoromethanesulfonic anhydride to
obtain triflate derivatives 10–12. A subsequent cross-
coupling reaction with various arylboronic acids was used
to obtain the unsymmetrical diarylquinazolines 13–17
(Scheme 3).
In a previous paper,18 we have mentioned the metallation of
substituted 4-(3H)-quinazolones with 1 equiv. of n-BuLi at
278 8C, followed by reaction of LTMP in excess (4 equiv.).
Under these conditions, lithiation was observed at the C8
´
position, peri to the ring nitrogen atom N1. We have
reinvestigated the conditions of metallation with compound
18,21 which presents a tert-butyl group on the C2 position.
This group avoids a nucleophilic attack of the metallating
agent at this position19–20 and prevents deprotonation on the
carbon Ca of the lateral chain.22–24 It could be noticed that
with such a product, alkyllithiums could be used as
metallating agent.
In the second synthetic route, the starting material was
2-tert-butyl-4(3H)-quinazolinone 18. In a first step, lithia-
tion and functionalization of the benzene moiety of 18 have
been performed regioselectively at the C5 position, then
further cross-coupling reactions allowed us to access to new
4,5-di(hetero)arylquinazolines (Scheme 4).
Treatment of 18 with n equivalents of LTMP (n¼4 to 8) at
0 8C for 1 h and acetaldehyde as electrophile did not allow
Scheme 3.

A. Busch et al. / Tetrahedron 60 (2004) 5373–5382
5375
Scheme 4.
Scheme 5.
Table 1. Metallation of compound 18
Entry
Metallating agent
nequiv.
Temperature (8C)
Time, t (h)
Starting material
(%)
18
19
1
2
3
4
5
6
n-BuLi
n-BuLi
n-BuLi
(n-BuLi/TMEDA)
(s-BuLi/TMEDA)
(s-BuLi/TMEDA)
3
3
4
4
4
4
278
0
0
220
278
220
1
1
1
2
1
1
64
60
28
22
62
6
36
40
72
78
38
94
any reaction and starting material has been recovered. So,
use of alkyllithiums was performed under various con-
ditions with acetaldehyde as electrophile, leading to
compound 19 (Scheme 5, Table 1).
2-tributylstannylpyridine following Stille cross-coupling
conditions and afforded 32 (Scheme 7).
The X-ray structure analysis of 14 (Fig. 1) shows that both
phenyl rings subtend angles of 62 and 688 with the plane of
quinazoline. Similarly high torsion angles are observed in
other diarylnaphthalenes14,17 and lead to face–face arrange-
ment of such p-electron systems. The very close approach
of the two phenyl rings is noteworthy: the value of 297.1 pm
observed for C9–C15 is slightly smaller than in the other
1,8-diphenylnaphthalenes and markedly smaller than the
van der Waals distance for parallel aromatic systems (about
345 pm).17b
The results given in Table 1 revealed that the best results
were obtained with 4 equiv. of s-BuLi and TMEDA at
220 8C for 1 h (entry 6), under these conditions, 19 was
obtained in good yield (94%) beside small amounts of
starting material.
Structure of compound 19 was established unambigously by
NMR experiments highlighting a regioselective metallation
at the C5 position. These conditions were used with other
electrophiles (Scheme 6).
As it has been previously mentioned in the literature,14
through-space interaction and lack of D/A conjugation with
possible D–A/D–A stacking, tend to favor the formation of
acentric structures. Thus 14 crystallizes in the non-
centrosymmetric space group P21, which renders such a
structure candidate to non-linear activity for a frequency-
doubling function.
Starting from compound 24, cross-coupling reactions were
performed under Suzuki conditions leading to 2-tert-butyl-
5-aryl-4-(3H)-quinazolones 25–27. These 4-oxo deriva-
tives were converted with phosphorus oxychloride to their
4-chloro derivatives 28–29. In a last step compounds 28 and
29 reacted with arylboronic acids to give the expected
compounds 30–31. Compound 28 was also reacted with
The NLO measurements of the mb values of compounds 15
Scheme 6.

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A. Busch et al. / Tetrahedron 60 (2004) 5373–5382
Scheme 7.
4,5-diarylquinazolines may have appreciable non-linear
optical properties. Further and complete measurements
will be performed with the other compounds.
1. Conclusion
We have synthesized eight new 4,5-di(hetero)aryl quinazo-
lines using cross-coupling reactions. The regioselective
functionalization of the C5 position of the 2-tert-butyl-
4(3H)-quinazolinone 18 allowed us to develop a second
synthetic route to access to compounds 29–31. The non-
linear optical properties of two compounds of these series
have been measured and interesting and promising results
have been observed. Synthesis of other new 4,5-di(hetero)-
aryl quinazolines and measurement of their first-order
hyperpolarizability b are in progress.
Figure 1. Crystal structure of 14. Selected distances (ppm): C4–C6 256.5;
C9–C15 297.1; N2–C1 241.9; C18–C12 435.6. Planar angles (8): C4–
C5–C6: 126.4. Interplanar angles (8) C5–C6/C15–C20: 61.7; C4–C5/C9–
C14: 68.0.
2. Experimental
Melting points were determined on a Kofler hot-stage. The
1H, 13C and 19F spectra were recorded on a Bruker AC 300
(300 MHz 1H, 75 MHz 13C, 282 MHz 19F) instrument.
Microanalyses were performed on a Carlo Erba CHNOS
1160 apparatus. The IR spectra were obtained as potassium
bromide pellets with a Perkin–Elmer Paragon 500
spectrophotometer.
and 17 have been performed by means of the EFISH method
(Table 2). The values mcalc are the computed ground-state
dipole moments calculated by AM1.
The high b values of these compounds 15, 17, compared
to paranitroanilin (PNA) (17£10230 esu)14a indicate that
All reagents were of commercial quality and were
purchased from Acros, Aldrich Chemical Co. or Avocado.
The Pd(0)-catalyst Pd(PPh3)4 was prepared according to the
literature.25 4-Trifluoromethyl-, 4-methoxyphenyl-, 4-N,N-
dimethylaminophenyl- and 4-cyanophenylboronic acids
were synthesized by halogen–metal exchange followed by
reaction with trimethylborate or triisopropylborate from the
commercially available 1-bromo-4-trifluoromethylbenzene,
Table 2. mcalcd (D): computed ground state dipole moments, experimental
mb values determined by EFISH measurements and evaluated first-order
hyperpolarizability b of compounds 15, 17
Compound
mcalcd (D)
mb£10248 esu
b£10230 esu
15
17
6.62
3.42
22.4
11.6
547
169

A. Busch et al. / Tetrahedron 60 (2004) 5373–5382
5377
4-bromoanisole, 4-bromo-N,N-dimethylaniline or 4-bromo-
benzonitrile.
(15 mL) was heated under reflux under nitrogen atmosphere
for a time t. After cooling, a mixture of water (10 mL) and
dichloromethane (10 mL) was added. The organic phase
was extracted with dichloromethane (3£20 mL). The
combined organic extracts were then dried over magnesium
sulphate and evaporated. The crude product was purified by
column chromatography on silica gel.
2.1. Procedure A for direct lithiation by lithium
alkylamide (LTMP)
A solution of n-butyllithium (1.6 or 2.5 M in hexane) was
added to cold (250 8C), stirred and anhydrous tetrahydro-
furan (15 mL) under an atmosphere of dry nitrogen. Then
2,2,6,6-tetramethylpiperidine (TMPH) was added. The
mixture was warmed to 0 8C. After 20 min, the temperature
was lowered to 278 8C and the substrate dissolved in 5 mL
of THF was added. After a time t1 at temperature T1, iodine
was introduced and stirring was continued for a time t2 at T2.
Hydrolysis was then carried out using a mixture of ethanol
and water (5/5). At room temperature, the solution was
decolorized with sodium thiosulphate. After concentration,
the residue was extracted with dichloromethane or ethyl
acetate (3£15 mL). The combined organic extracts were
dried over magnesium sulfate and evaporated. The crude
product was purified by column chromatography on silica
gel.
2.4.1. 4-Chloro-5-methoxyquinazoline (3). Reaction of
2
(1.5 g, 8.5 mmol) with phosphorus pentachloride
(1.5 equiv.) in POCl3 (30 mL) under reflux for 15 h,
followed by removal of excess of POCl3 under reduced
pressure. The residue was dissolved in CH2Cl2 (20 mL),
then poured on ice and neutralized by an aqueous Na2CO3
solution. The aqueous phase was extracted with dichloro-
methane (3£20 mL), the combined organic extracts were
then dried over magnesium sulfate and evaporated. The
crude product purified by column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate 2/8) gave after
purification 1.1 g (66%) of 3 as a white solid, mp 113–
1
114 8C; H NMR (CDCl3): d 8.84 (s, 1H, H2); 7.73 (dd,
J¼8.3, 7.9 Hz, 1H, H7); 7.52 (d, J¼8.3 Hz, 1H, HPh); 7.08
(d, J¼7.9 Hz, 1H, HPh); 3.94 (s, 3H, OCH3). Anal. calcd for
C9H7ClN2O (194.62): C, 55.54; N, 14.39; H, 3.63. Found:
C, 55.53; N, 14.40; H, 3.89.
2.2. Procedure B for direct lithiation by sec-butyl-
lithium/tetramethylethylenediamine (sec-butyllithium/
TMEDA
2.4.2. 5-Methoxy-4-(40-trifluoromethylphenyl)quinazo-
line (4). Cross-coupling reaction of 4-trifluoromethyl-
phenylboronic acid (1.3 equiv.) with 3 (390 mg, 2 mmol)
according to the general procedure C (t¼40 h) gave after
purification by column chromatography (silica gel, eluent:
petroleum ether/ethyl acetate 5/5) 445 mg (71%) of 4 as a
pale yellow solid, mp 94–95 8C; 1H NMR (CDCl3): d 9.32
(s, 1H, H2); 7.88–7.61 (m, 5H, 5Har); 6.95 (d, J¼7.7 Hz,
2H, 2HPhCF3); 3.64 (s, 3H, OCH3); 19F NMR (CDCl3):
A solution of sec-butyllithium (1.3 M in hexane) was added
to cold stirred and anhydrous tetrahydrofuran (20 mL) under
an atmosphere of dry nitrogen. Then tetramethylethylene-
diamine (TMEDA) was added. The mixture was cooled to
278 8C and added to a solution of 2-tert-butylquinazolin-
4(3H)-one 18 in THF. After a time t1 at temperature T1, the
electrophile was introduced and the mixture was keeped at
T2 for a time t2. Hydrolysis was then carried out using a
solution of ethanol and water (5/5) at 278 8C. At room
temperature, water (10 mL) was added to the mixture and
THF was removed under reduced pressure. The aqueous
layer was extracted with dichloromethane or ethyl acetate
(3£20 mL), the combined organic extracts were then dried
over magnesium sulfate and evaporated. The crude product
was purified by column chromatography on silica gel.
262.8; IR: n 1614, 1573, 1331, 1122, 1067, 831 cm21
.
Anal. calcd for C16H11F3N2O (304.27): C, 63.16; N, 9.21;
H, 3.63. Found: C, 62.81; N, 9.52; H, 3.99.
2.4.3. 5-Methoxy-4-(30-nitrophenyl)quinazoline (5).
Cross-coupling reaction of 3-nitrophenylboronic acid
(1.3 equiv.) with 3 (390 mg, 2 mmol) according to the
general procedure C (t¼62 h) gave after purification by
column chromatography (silica gel, eluent: petroleum ether/
ethyl acetate 5/5) 348 mg (62%) of 5 as a white solid, mp
172–173 8C; 1H NMR (CDCl3): d 9.32 (s, 1H, H2); 8.40 (s,
1H, HPhNO2); 8.34 (d, J¼8.2 Hz, 1H, HPh); 7.89 (m, 2H,
2HPh); 7.77–7.64 (m, 2H, 2HPh); 6.97 (d, J¼7.7 Hz, 1H,
Har); 3.65 (s, 3H, OCH3); IR: n 1571, 1525, 1350,
691 cm21. Anal. calcd for C15H11N3O3 (281.27): C,
64.05; N, 14.94; H, 3.94. Found: C, 63.74; N, 14.86; H, 4.32.
2.3. Procedure C for cross-coupling of arylboronic acids
with heteroaryl halide under Suzuki conditions
A mixture of the heteroaryl halide (2 mmol), the arylboronic
acid (1.3 equiv.), Pd(PPh3)4 (0.05 equiv.), aqueous 2 M
potassium carbonate (2 equiv.) and DME (12 mL) and H2O
(3 mL) or ethanol (1 mL) in degassed toluene (15 mL) was
heated under reflux and under nitrogen for 15–48 h. The
reaction mixture was cooled, diluted with 15 mL of water
and dichloromethane (1/1) and the organic layers separated.
The aqueous layer was extracted with dichloromethane
(3£15 mL), the combined organic extracts were dried over
magnesium sulfate and evaporated. The crude product was
purified by column chromatography on silica gel.
2.4.4. 5-Methoxy-4-(20-pyridyl)quinazoline (6). Cross-
coupling reaction of (2-pyridyl)-tributylstannane (1.3 equiv.)
with 3 (390 mg, 2 mmol) according to the general procedure
D (t¼50 h) gave after purification by column chromatog-
raphy (silica gel, eluent: petroleum ether/ethyl acetate 2/1)
431 mg (91%) of 6 as a pale yellow solid, mp 115–116 8C;
1H NMR (CDCl3): d 9.24 (s, 1H, H2); 8.61 (dd, J¼4.9,
2.4. Procedure D for cross-coupling of heteroaryl halides
with tributylstannylheteroarene under Stille conditions
0
0
0.75 Hz, 1H, H6 ); 7.75 (m, 2H, H7/4 ); 7.62 (d, J¼8.3 Hz,
0
0
1H, H8); 7.45 (m, 1H, H3 ); 7.29 (m, 1H, H5 ); 6.82 (d,
J¼7.9 Hz, 1H, H6); 3.49 (s, 3H, OCH3)); 13C NMR
(CDCl3): d 165.5, 159.4, 156.2, 154.4 (C2), 152.7, 148.6
A solution of tributylstannylheteroarene, arylhalide
(0.8 equiv.) and Pd(PPh3)4 (0.05 equiv.) in degassed toluene

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A. Busch et al. / Tetrahedron 60 (2004) 5373–5382
(CH), 136.0 (CH), 134.8 (CH), 123.1 (CH), 122.8 (CH),
120.9 (CH), 115.6, 107.3 (CH), 55.9 (OCH3). Anal. calcd
for C14H11N3O (237.26): C, 70.87; N, 17.71; H, 4.67.
Found: C, 71.32; N, 18.12; H, 4.56.
reflux for 15 h. After cooling and hydrolysis with 10 mL of
water and neutralization with saturated aqueous sodium
carbonate solution, the mixture was extracted with dichloro-
methane (3£15 mL). The combined organic extracts were
dried over magnesium sulfate and evaporated. Purification
by column chromatography (silica gel, eluent: petroleum
ether/ethyl acetate (5/5)) afforded 476 mg (71%) of 10 as a
2.4.5. 5-Hydroxy-4-(40-trifluoromethylphenyl)quinazo-
line (7). A mixture of 4 (625 mg, 2.1 mmol) and pyridinium
chloride (5 g) was heated to 210 8C for 1 h 30 min. After
cooling, the mixture was poured onto ice and neutralized
with a 10% ammoniac solution. The aqueous layer was
extracted with ethyl acetate (5£20 mL), the combined
organic extracts were dried over magnesium sulfate and
evaporated. The crude product was washed with dichloro-
methane and 7 (488 mg, 79%) was obtained as a brown
solid, mp 230–231 8C; 1H NMR (d6-DMSO): d 10.83 (1H,
OH); 9.22 (s, 1H, H2); 7.75 (m, 5H, 4HPhCF3 and H7); 7.52
(d, J¼8.3 Hz, 1H, Har); 7.03 (d, J¼7.7 Hz, 1H, Har); IR: n
3052, 1572, 1498, 1329, 1169, 1068, 850, 828 cm21. Anal.
calcd for C15H9F3N2O (290.24): C, 62.07; N, 9.65; H, 3.13.
Found: C, 62.10; N, 9.84; H, 3.44.
1
brown solid, mp 98–99 8C; H NMR (CDCl3): d 9.45 (s,
1H, H2); 8.26 (d, J¼8.4 Hz, 1H, H8); 8.01 (dd, J¼8.4,
7.7 Hz, 1H, Har); 7.89 (m, 4H, 4HPhCF3); 7.62 (d, J¼7.7 Hz,
1H, Har); 19F NMR (CDCl3): d 263.2, 273.1; IR: n 1543,
1402, 1332, 1220, 1131, 1064, 838, 822 cm21. Anal. calcd
for C16H8F6N2SO3 (422.31): C, 45.51; N, 6.63; H, 1.91; S,
7.59. Found: C, 45.32; N, 6.39; H, 2.03; S, 7.56.
2.4.9. 4-(30-Nitrophenyl)-5-trifluoromethylsulfonyloxy-
quinazoline (11). A mixture of 8 (270 mg, 1.01 mmol),
triethylamine (0.43 mL, 3 equiv.) and trifluromethanesul-
fonic anhydride (0.34 mL, 2 equiv.) dissolved in 10 mL of
anhydrous dichloromethane was heated under reflux for
15 h. After cooling and hydrolysis with 10 mL of water and
neutralization with saturated aqueous sodium carbonate
solution, the mixture was extracted with dichloromethane
(3£15 mL). The combined organic extracts were dried over
magnesium sulfate and evaporated. Purification by column
chromatography (silica gel, eluent: petroleum ether/ethyl
acetate (5/5)) afforded 110 mg (25%) of 11 as an orange oil;
1H NMR (CDCl3): d 9.46 (s, 1H, H2); 8.50–8.40 (m, 2H,
2HPhNO2); 8.28 (d, J¼8.5 Hz, 1H, 1Har); 8.04 (m, 2H, H7/
PhNO2); 7.74 (t, J¼8 Hz, 1H, 1HPhNO2); 7.64 (d, J¼7.8 Hz,
1H, Har); 19F NMR (CDCl3): d 273.0; IR: n 3418, 1623,
1532, 1428, 1350, 1217, 1136 cm21. Anal. calcd for
C15H8N3SO5 (399.31): C, 45.12; N, 10.52; H, 2.02; S,
8.01. Found: C, 45.38; N, 10.25; H, 2.38; S, 7.97.
2.4.6. 5-Hydroxy-4-(30-nitrophenyl)quinazoline (8). A
mixture of 5 (400 mg, 1.4 mmol) and pyridinium chloride
(5 g) was heated to 210 8C for 1 h 30 min. After cooling, the
mixture was poured onto ice and neutralized with a 10%
ammoniac solution. The aqueous layer was extracted with
ethyl acetate (3£20 mL), the combined organic extracts
were dried over magnesium sulfate and evaporated. The
crude product was washed with dichloromethane and 8
(277 mg, 73%) was obtained as a brown solid, mp .260 8C;
1H NMR (d6-DMSO): d 9.23 (s, 1H, H2); 8.34 (m, 2H,
2HPhNO2); 8.02 (m, 1H, HPhNO2); 7.85 (dd, J¼8.4, 8 Hz, 1H,
1HPhNO2); 7.74 (dd, J¼8, 7.6 Hz, 1H, H7); 7.54 (d, J¼8 Hz,
1H, Har); 7.02 (d, J¼7.6 Hz, 1H, Har); IR: n 3070, 1526,
1502, 1347, 830, 692 cm21. Anal. calcd for C14H9N3O3
(267.24): C, 62.92; N, 15.72; H, 3.39. Found: C, 63.16; N,
15.77; H, 3.65.
2.4.10. 4-(20-Pyridyl)-5-trifluoromethylsulfonyloxyquin-
azoline (12). A mixture of 9 (120 mg, 0.54 mmol),
triethylamine (0.22 mL, 3 equiv.) and trifluromethanesulfo-
nic anhydride (0.19 mL, 1 equiv.) dissolved in 10 mL of
anhydrous dichloromethane was heated under reflux for
15 h. After cooling and hydrolysis with 10 mL of water and
neutralization with saturated aqueous sodium carbonate
solution, the mixture was extracted with dichloromethane
(3£15 mL). The combined organic extracts were dried over
magnesium sulfate and evaporated. Purification by column
chromatography (neutral alumina, eluent: ethyl acetate)
afforded 95 mg (49%) of 12 as a brown solid, mp 74–75 8C;
1H NMR (CDCl3): d 9.38 (s, 1H, H2)); 8.66 (dd, J¼4.9,
2.4.7. 5-Hydroxy-4-(20-pyridyl)quinazoline (9). A mixture
of 6 (200 mg, 0.84 mmol) and pyridinium chloride (5 g) was
heated to 210 8C for 1 h 30 min. After cooling, the mixture
was poured onto with ice and neutralized with a 10%
ammoniac solution. The aqueous layer was extracted with
ethyl acetate (3£50 mL), the combined organic extracts
were dried over magnesium sulfate and evaporated.
Purification by column chromatography (neutral alumina,
eluent: petroleum ether/ethyl acetate (5/5)) afforded 116 mg
1
(62%) of 77 as an orange solid, mp 120–121 8C; H NMR
(CDCl3): d 15.57 (1H, OH); 9.20 (s, 1H, H2); 8.83 (dd, J¼
0
1.1 Hz, 1H, H6 ); 8.14 (dd, J¼8.7, 1.1 Hz, 1H, Har); 7.97–
0
0
0
0
8.3, 0.75 Hz, 1H, H3 ); 8.61 (dd, J¼4.9, 0.75 Hz, 1H, H6 );
7.86 (m, 3H, H3 ,4 ,7); 7.54 (d, J¼7.9 Hz, 1H, Har); 7.41 (m,
8.03 (m, 1H, H4 ); 7.76 (dd, J¼8.3, 7.9 Hz, 1H, H7); 7.55–
1H, H5 ); 19F NMR (CDCl3): d 273.2; 13C NMR (CDCl3): d
0
0
7.51 (m, 2H, H5 /8); 7.10 (dd, J¼7.9, 1.1 Hz, 1H, H6) 13C
164.7, 156.9, 154.8 (CH), 153.1, 149.5 (CH), 144.2, 137.5
(CH), 133.6 (CH), 130.3 (CH), 125.1 (2£CH), 121.5
(CH), 117.5, 30.1 (CF3). HRMS(IC) calculated for
C14H8F3N3O3S: 356.0317. Found: 356.0319.
0
NMR (CDCl3): d 160.3, 155.1, 154.9, 153.0, 152.0 (C2),
0
0
0
144.4 (C3 ), 138.9 (C5 ), 134.7 (C7), 126.5 (C6 ), 125.1 (CH),
118.6 (CH), 115.3 (C4a), 114.3 (CH); IR: n 3059, 1564,
1522, 1480, 1418, 1352, 1274, 831, 796 cm21. HRMS(IC)
calculated for C13H10N3O: 224.0824. Found: 224.0829.
2.4.11. 5-Phenyl-4-(40-trifluoromethylphenyl)quinazo-
line (13). Cross-coupling reaction of phenylboronic acid
(1.3 equiv.) with 10 (200 mg, 0.47 mmol) according to the
general procedure C (t¼38 h) gave after purification by
column chromatography (silica gel, eluent: petroleum ether/
ethyl acetate 5/5) 120 mg (72%) of 13 as a white solid, mp
2.4.8. 4-(40-Trifluoromethylphenyl)-5-trifluoromethyl-
sulfonyloxyquinazoline (10). A mixture of 7 (460 mg,
1.59 mmol), triethylamine (0.67 mL, 3 equiv.) and trifluro-
methanesulfonic anhydride (0.53 mL, 2 equiv.) dissolved in
12 mL of anhydrous dichloromethane was heated under
1
133–134 8C; H NMR (CDCl3): d 9.41 (s, 1H, H2); 8.20

A. Busch et al. / Tetrahedron 60 (2004) 5373–5382
5379
(dd, J¼8.4, 1.2 Hz, 1H, H8); 8.00 (dd, J¼8.4, 7.2 Hz, 1H,
19F NMR (CDCl3): d 263.3; IR: n 1537, 1325, 1108, 1065,
828, 706 cm21. Anal. calcd for C19H11F3N2S (394.48): C,
64.04; N, 7.86; H, 3.11. Found: C, 64.31; N, 7.59; H, 3.46.
0
0
0
H7); 7.67 (dd, J¼7.2, 1.2 Hz, 1H, H6); 7.28 (m, 4H, H2 /3 /5 /
6 ); 7.01 (m, 5H, 5HPh); 19F NMR (CDCl3): d 263.4; IR: n
0
1537, 1324, 1108, 1065, 836, 762, 699 cm21. Anal. calcd
for C21H13F3N2 (350.34): C, 72.00; N, 8.00; H, 3.74. Found:
C, 72.30; N, 7.73; H, 3.82.
2.4.16. 2-tert-Butyl-5-(1-hydroxyethyl)quinazolin-4(3H)-
one (19). Metallation of 18 (50 mg, 0.24 mmol) according
to the procedure B with sec-BuLi 1.3 M (4.2 equiv.,
0.80 mL), TMEDA (4.0 equiv., 0.149 mL), T1¼278 8C,
followed by reaction with acetaldehyde (5 equiv., 0.07 mL),
t1¼1 h, gave after purification by column chromatography
(silicagel, eluent: dichloromethane/ethyl acetate (1/1))
2.4.12. 5-(400-Methoxyphenyl)-4-(40-trifluoromethyl-
phenyl)quinazoline (14). Cross-coupling reaction of
4-methoxyphenylboronic acid (1.3 equiv.) with 10
(200 mg, 0.47 mmol) according to the general procedure
C (t¼38 h) gave after purification by column chromatog-
raphy (silica gel, eluent: petroleum ether/ethyl acetate 5/5)
155 mg (86%) of 14 as a pale yellow solid, mp 45–46 8C;
1H NMR (CDCl3): d 9.40 (s, 1H, H2); 8.18 (dd, J¼8.4,
1.2 Hz, 1H, H8); 7.99 (dd, J¼8.4, 7.2 Hz, 1H, H7); 7.66 (dd,
1
49 mg (82%) of 19 as a white solid, mp 189–190 8C; H
NMR (CDCl3): d 10.94 (s, 1H, NH); 7.64 (m, 2H, H7 and
H8); 7.46 (dd, JH6–H7¼6.41 Hz and JH6–H8¼2.26 Hz, 1H,
H6); 5.45 (quint, J¼6.78 Hz, 1H, CHOH); 5.07 (d, J¼
7.54 Hz, 1H, OH); 1.57 (d, J¼6.78 Hz, 3H, Me); 1.43 (s,
9H, tert-butyl); 13C NMR (CDCl3): d 165.4 (Cqui), 161.8
(Cqui), 152.1 (Cqui), 147.3 (Cqui), 134.9 (CHqui), 128.3
(CHqui), 125.4 (CHqui), 117.9 (Cqui), 69.66 (CHOH), 37.5
(CMe3), 28.6 (3Metert-butyl), 23.8 (Me). Anal. calcd for
C14H18N2O2 (246.30): C, 68.27; H, 7.37; N, 11.99. Found:
C, 67.97; H, 7.31; N, 11.61.
0
0
0
0
J¼7.2, 1.2 Hz, 1H, H6); 7.32 (m, 4H, H2 /3 /5 /6 ); 6.90
(d, J¼6.7 Hz, 2H, 2HPhOCH3); 6.54 (d, J¼6.7 Hz, 2H,
2HPhOCH3); 19F NMR (CDCl3): d 263.3; IR: n 1611, 1514,
1324, 1164, 1066, 831 cm21. Anal. calcd for C22H15F3N2O
(380.37): C, 69.47; N, 7.36; H, 3.97. Found: C, 69.35; N,
7.17; H, 3.58.
2.4.13. 5-(400-Methoxyphenyl)-4-(30-nitrophenyl)quinazo-
line (15). Cross-coupling reaction of 4-methoxyphenyl-
boronic acid (1.3 equiv.) with 11 (100 mg, 0.25 mmol)
according to the general procedure C (t¼86 h) gave after
purification by column chromatography (silica gel, eluent:
ethyl acetate) 70 mg (79%) of 15 as a pale yellow solid, mp
136–137 8C; 1H NMR (CDCl3): d 9.42 (s, 1H, H2); 8.20 (d,
J¼7.9 Hz, 1H, Har); 8.03 (m, 2H, 2Har); 7.68 (d, J¼7.3 Hz,
1H, Har); 7.36 (t, J¼7.9 Hz, 1H, Har); 6.94 (d, J¼8.5 Hz,
2.4.17. 2-tert-Butyl-5-(1-hydroxyphenyl)quinazolin-
4(3H)-one (20). Metallation of 18 (50 mg, 0.24 mmol)
according to the procedure B with sec-BuLi 1.3 M
(4.2 equiv., 0.80 mL), TMEDA (4.0 equiv., 0.149 mL),
T1¼278 8C, followed by reaction with benzaldehyde
(5 equiv., 0.126 mL), t1¼1 h, gave after purification by
column chromatography (silicagel, eluent: dichloro-
methane/ethyl acetate (8/2)) 70 mg (92%) of 20 as a white
1
solid, mp 163–164 8C; H NMR (CDCl3): d 10.76 (s, 1H,
00 00
00 00
2H, H2 /6 ); 6.53 (d, J¼8.5 Hz, 2H, H3 /5 ); 3.70 (s, 3H,
NH); 7.61 (m, 2H, H7 and H8); 7.24 (m, 5H, Ph); 7.13 (dd,
JH6–H7¼7.16 Hz and JH6–H8¼1.51 Hz, 1H, H6); 6.39 (d,
J¼7.91 Hz, 1H, CHOH); 5.73 (d, J¼7.91 Hz, 1H, OH); 1.34
(s, 9H, tert-butyl); 13C NMR (CDCl3): d 165.2 (Cqui), 161.9
(Cqui), 152.2 (Cqui), 145.1 (Cqui), 143.3 (CPh), 134.7 (CHqui),
128.8 (CHqui), 128.4 (2CHPh), 128.3 (CHPh), 127.5 (CHqui),
127.2 (2CHPh), 118.5 (Cqui), 75.1 (CHOH), 37.5 (CMe3),
28.5 (3Metert-butyl). Anal. calcd for C19H20N2O2 (308.38):
C, 74.00; H, 6.54; N, 9.08. Found: C, 74.13; H, 6.56; N,
8.69.
OCH3); IR: n 1529, 1511, 1351, 1241, 1028, 806, 692 cm21
.
Anal. calcd for C21H15N3O3 (357.37): C, 70.59; N, 11.76;
H, 4.20. Found: C, 70.95; N, 11.41; H, 4.55.
2.4.14. 5-(400-Methoxyphenyl)-4-(20-pyridyl)quinazoline
(16). Cross-coupling reaction of 4-methoxyphenylboronic
acid (1.3 equiv.) with 12 (125 mg, 0.35 mmol) according to
the general procedure C (t¼60 h) gave after purification by
column chromatography (silica gel, eluent: petroleum ether/
ethyl acetate 5/5) 31 mg (28%) of 16 as a yellow solid, mp
106–107 8C; 1H NMR (CDCl3): d 9.35 (s, 1H, H2); 8.20 (d,
2.4.18. 2-tert-Butyl-5-phenylsulfanylquinazolin-4(3H)-
one (21). Metallation of 18. (50 mg, 0.24 mmol) according
to the procedure B with sec-BuLi 1.3 M (4.2 equiv.,
0.80 mL), TMEDA (4.0 equiv., 0.149 mL), T1¼278 8C,
followed by reaction with benzaldehyde (5 equiv.,
0.126 mL), t1¼1 h, gave after purification by column
chromatography (silicagel, eluent: petromeum ether/ethyl
acetate (7/3)) 13 mg (17%) of 21 as a white solid, mp
.250 8C; 1H NMR (CDCl3): d 10.85 (s, 1H, NH); 7.57 (m,
2H, H7 and H8); 7.42 (m, 3H); 7.29 (d, J¼4.52 Hz, 2H); 6.51
(dq, J¼4.53 Hz, 1H); 1.42 (s, 9H, tert-butyl); 13C NMR
(CDCl3): d 164.2 (Cqui)162.5 (Cqui), 151.3 (Cqui), 144.2
(Cqui), 136.7 (2CHPh), 133.9 (CHqui), 132.5 (Cqui), 130.3
(2CHPh), 129.8 (CHqui), 123.7 (CH),123.3 (CH), 37.7
(CMe3), 28.6 (3Metert-butyl). Anal. calcd for C18H18N2OS
(310.42): C, 69.65; H, 5.84; N, 9.02; S, 10.33. Found: C,
69.37; H, 5.93; N, 8.87; S, 10.58.
0
J¼3.8 Hz, 1H, H6 ); 8.07 (dd, J¼8.7 and 1.1 Hz, 1H, H8);
7.90 (dd, J¼8.7, 7.1 Hz, 1H, H7); 7.56 (dd, J¼7.1, 1.5 Hz,
0
1H, H6); 7.42–7.32 (m, 2H, H3 /4 ); 6.94–6.91 (m, 3H,
0
00 00
0
00 00
H2 /6 /5 ); 6.49 (d, J¼8.7 Hz, 2H, H3 /5 ); 3.71 (s, 3H,
OCH3); IR: n 1606, 1565, 1512, 1465, 1359, 1246, 1031,
799 cm21. Anal. calcd for C20H15N3O (313.36): C, 76.46;
N, 13.41; H, 4.82. Found: C, 76.22; N, 12.98; H, 4.44.
2.4.15. 5-(200-Thienyl)-4-(40-trifluoromethylphenyl)quin-
azoline (17). Cross-coupling reaction of (2-thienyl)-tri-
methylstannane (1.3 equiv.) with 10 (150 mg, 0.36 mmol)
according to the general procedure D (t¼24 h) gave after
purification by column chromatography (silica gel, eluent:
petroleum ether/ethyl acetate 5/5) 85 mg (67%) of 17 as a
1
pale yellow solid, mp 137–138 8C; H NMR (CDCl3): d
9.41 (s, 1H, H2); 8.19 (dd, J¼8.4, 1.2 Hz, 1H, H8); 7.98 (dd,
J¼8.4, 7.2 Hz, 1H, H7); 7.77 (dd, J¼7.2, 1.2 Hz, 1H, H6);
0
0
0
0
00
7.43 (m, 4H, H2 /3 /5 /6 ); 7.09 (dd, J¼5, 1 Hz, 1H, H5 ); 6.56
2.4.19. 2-tert-Butyl-5-(tri-n-butylstannyl)quinazolin-
4(3H)-one (22). Metallation of 18 (50 mg, 0.24 mmol)
00
00
(dd, J¼5, 3.6 Hz, 1H, H4 ); 6.39 (dd, J¼3.6, 1 Hz, 1H, H3 );

5380
A. Busch et al. / Tetrahedron 60 (2004) 5373–5382
according to the procedure B with sec-BuLi 1.3 M
(4.2 equiv., 0.80 mL), TMEDA (4.0 equiv., 0.149 mL),
T1¼278 8C, followed by reaction with tri-n-butylstannyl
chloride (5 equiv., 0.34 mL), t1¼1 h, gave after purification
by column chromatography (silicagel, eluent: petroleum
ether/ethyl acetate (7/3)) 13 mg (17%) of 22 as a vitrous
solid, mp 54–55 8C; 1H NMR (CDCl3): d 8.72 (s, 1H, NH);
7.59 (m, 3H, H6/7/8); 1.48 (m, 6H, CH2); 1.34 (s, 9H, tert-
butyl); 1.13 (2m, 12H, CH2); 0.79 (t, J¼7.16–7.54 Hz, 9H,
CH3); 13C NMR (CDCl3): d 164.2 (Cqui), 160.5 (Cqui), 149.5
(Cqui), 145.1 (Cqui), 135.8 (CHqui), 134.0 (CHqui), 127.9
(CHqui), 125.5 (Cqui), 37.4 (Ctert-butyl), 29.6 (CH2), 28.7
(3£CH3tert-butyl), 27.8 (CH2), 14.1 (CH3), 11.8 (CH2). Anal.
calcd for C24H40N2OSn (491.30): C, 58.67; H, 8.21; N, 5.70.
Found: C, 58.68; H, 8.23; N, 5.27.
C19H20N2O2 (308.38): C, 74.00; N, 9.08; H, 6.54. Found: C,
73.88; N, 8.82; H, 6.34.
2.4.23. 2-tert-Butyl-5-(20-thienyl)quinazolin-4(3H)-one
(26). Coupling of heteroarylboronic acid 24 (640 mg,
1.3 equiv.) with 2-iodothiophene (421 mg, 2 mmol) accord-
ing to the general procedure F (DME, t¼60 h) gave after
purification by column chromatography (silica gel, eluent
petroleum ether/ethyl acetate 7/3) 341 mg (60%) of 26 as a
beige solid, mp 242–243 8C; 1H NMR (CDCl3): d 11.87 (s,
0
1H, NH); 7.70 (m, 2H, H6/8); 7.35 (m, 2H, H2 /7); 7.03 (m,
0
2H, H3 /4 ); 1.25 (s, 9H, tert-butyl); 13C NMR (CDCl3): d
0
0
163.7 (C4), 163.1 (C2), 150.9 (C8a), 142.8 (C5), 135.5 (C1 ),
0
133.0 (C6), 131.1 (C7), 128.7 (C8), 126.8 (C3 or C4 ), 126.6
0
0
0
0
(C3 or C4 ), 125.2 (C2 ), 118.8 (C4a), 37.2 (Ctert-butyl), 28.3
(3£CH3tert-butyl); IR: n 3175, 1660, 1614, 1592, 1570, 1310,
976, 822, 786 cm21. Anal. calcd for C16H16N2OS (284.38):
C, 67.58; N, 9.85; H, 5.67. Found: C, 67.23; N, 9.37; H,
5.13.
2.4.20. 2-tert-Butyl-5-iodoquinazolin-4(3H)-one (23).
Metallation of 18 (50 mg, 0.24 mmol) according to the
procedure B with sec-BuLi 1.3 M (4.2 equiv., 0.80 mL),
TMEDA (4.0 equiv., 0.149 mL), T1¼278 8C, followed by
reaction with iodine in THF (5 equiv., 314 mg), t1¼1 h,
gave after purification by column chromatography (silica-
gel, eluent: ethyl ether/dichloromethane (1/9)) 30 mg (37%)
of 23 as a white solid, mp 245–246 8C; 1H NMR (CDCl3): d
11.40 (s, 1H, NH); 7.99 (dd, JH6–H7¼7.53–7.53 Hz and
JH6–H8¼0.75–1.13 Hz, 1H, H6); 7.63 (dd, JH8–H7¼7.91–
8.29 Hz and JH8–H6¼0.75–1.13 Hz, 1H, H8); 7.24 (t,
J¼7.9 Hz, H7); 1.44 (s, 9H, tert-butyl); 13C NMR
(CDCl3): d 162.7 (Cqui), 162.6 (Cqui), 151.0 (Cqui), 140.9
(CHqui), 135.0 (CHqui), 129.2 (CHqui), 120.4 (Cqui), 91.3
(Cqui), 38.0 (Ctert-butyl), 28.6 (3£CH3tert-butyl). Anal. calcd
for C12H13N2OI (328.15): C, 43.92; H, 3.99; N, 8.54. Found:
C, 43.98; H, 3.97; N, 8.35.
2.4.24. 2-tert-Butyl-5-(40-N,N-dimethylaminophenyl)-
quinazolin-4(3H)-one (27). Coupling of heteroarylboronic
acid 24 (640 mg, 1.3 equiv.) with 4-bromo-N,N-dimethyl-
aniline (400 mg, 2 mmol) according to the general pro-
cedure F (DME, t¼60 h) gave after purification by
recrystalization in diethyl ether 454 mg (71%) of 27 as a
solid, mp .250 8C; 1H NMR (CDCl3): d 11.33 (s, 1H, NH);
0
0
7.64 (m, 2H, H6/8); 7.20 (m, 3H, H2 /6 /7); 6.74 (d, J¼8.7 Hz,
0
0
2H, H3 /5 ); 3.00 (s, 6H, N(CH3)2); 1.22 (s, 9H, tert-butyl);
13C NMR (CDCl3): d 163.9 (C4), 162.6 (C2), 151.0 (C8a),
0
0
144.2 (C5), 133.4 (C6), 130.6 (C7), 129.9 (C1 ), 129.8 (C2 ,
0
0
0
C6 ), 126.9 (C8), 118.0 (C4a), 111.9 (C3 , C5 ), 40.9 (2£CH3),
37.2 (Ctert-butyl), 28.5 (3£CH3tert-butyl). Anal. calcd for
C20H23N3O (321.43): C, 74.74; N, 13.07; H, 7.21. Found:
C, 74.52; N, 12.60; H, 6.98.
2.4.21. 2-tert-Butyl-4-oxo-3,4-dihydroquinazolin-5-boro-
nic acid (24). Metalation of 18 (100 mg, 0.5 mmol)
according to the procedure B with sec-BuLi 1.3 M
(4.2 equiv., 1.6 mL), TMEDA (4.0 equiv., 0.3 mL),
T1¼220 8C, t1¼1 h, followed by reaction with tri-isopro-
pylborate (6 equiv., 564 mg), T2¼278 8C to rt, t2¼15 h,
gave after purification by washing with DCM 84 mg
2.4.25. 2-tert-Butyl-4-chloro-5-(40-methoxyphenyl)quin-
azoline (28). Reaction of 25 (900 mg, 2.9 mmol) with
POCl3 (50 mL) under reflux for 6 h, followed by removal of
excess of POCl3 under reduced pressure and partitionning of
the residue between CH2Cl2 and cold aqueous K2CO3
solution, gave after purification by column chromatography
(silica gel, eluent petroleum ether/ethyl acetate 6/4) 682 mg
1
(68%)of 24, mp 8C; H NMR (d6-DMSO): d 11.88 (s, 1H,
NH), 9.35 (s, 2H, 2£OH), 7.72 (t, J¼7.9 Hz, 1H, H7), 7.54
(dd, J¼7.9, 1.1 Hz, 1H, HAr), 7.42 (dd, J¼7.9, 1.1 Hz, 1H,
HAr), 1.37 (s, 9H, tert-butyl); IR: n 3346, 3173, 3069, 2973,
1
(72%) of 28 as a yellow solid, mp 98–99 8C; H NMR
(CDCl3): d 8.01 (d, J¼8.3 Hz, 1H, H8); 7.82 (dd, J¼8.3,
2922, 1640, 1583, 1409, 1375 cm21
.
7.2 Hz, 1H, H7); 7.47 (d, J¼7.2 Hz, 1H, H6); 7.24 (d,
0
0
0
0
J¼8.3 Hz, 2H, H2 /6 ); 6.96 (d, J¼8.3 Hz, 2H, H3 /5 ); 3.89 (s,
2.4.22. 2-tert-Butyl-5-(40-methoxyphenyl)quinazolin-
4(3H)-one (25). Coupling of heteroarylboronic acid 24
(640 mg, 1.3 equiv.) with 4-iodoanisole (468 mg, 2 mmol)
according to the general procedure C (DME, t¼60 h) gave
after purification by column chromatography (silica gel,
eluent petroleum ether/ethyl acetate 6/4) 246 mg (40%) of
25 as a white solid, mp .250 8C; 1H NMR (CDCl3): d 11.17
(s, 1H, NH); 7.66 (m, 2H, H6/8); 7.22 (d, J¼8.7 Hz, 2H,
3H, OCH3); 1.50 (s, 9H, tert-butyl); 13C NMR (CDCl3): d
0
171.9 (C2), 160.7 (C4), 159.2 (C4 ), 152.8 (C8a), 140.2 (C5),
0
0
133.5 (C1 ), 132.7 (C6), 131.0 (C2 , C6 ), 130.5 (C8),
0
0
0
128.3 (C7), 120.1 (C4a), 113.2 (C3 , C5 ), 55.3 (OCH3),
39.2 (Ctert-butyl), 29.3 (3£CH3tert-butyl); IR: n 1608, 1563,
1510, 1460, 1290, 1240, 1170, 881, 832, 744 cm21. Anal.
calcd for C19H19ClN2O (326.83): C, 69.83; N, 8.57; H, 5.86.
Found: C, 69.87; N, 8.49; H, 5.98.
0
0
0
0
H2 /6 ); 7.19 (t, 1H, H7); 6.89 (d, J¼8.7 Hz, 2H, H3 /5 ); 3.86
(s, 3H, OCH3); 1.18 (s, 9H, tert-butyl); 13C NMR (CDCl3):
2.4.26. 2-tert-Butyl-4-chloro-5-(20-thienyl)quinazolin-
4(3H)-one (29). Reaction of 26 (284 mg, 1 mmol) with
POCl3 (15 mL) under reflux for 6 h, followed by removal of
excess of POCl3 under reduced pressure and partitionning of
the residue between CH2Cl2 and cold aqueous K2CO3
solution, gave after purification by column chromatography
(silica gel, eluent petroleum ether/ethyl acetate 7/3) 121 mg
0
d 163.9 (C4), 162.8 (C2), 158.8 (C4 ), 151.0 (C8a), 143.5
0
(C5), 135.0 (C1 ), 133.4 (C6), 130.1 (C2 , C6 ), 129.9 (C7),
0
0
0
0
127.6 (C8), 118.1 (C4a), 113.2 (C3 , C5 ), 55.5 (OCH3), 37.2
(Ctert-butyl), 28.4 (3£CH3tert-butyl); IR: n 3173, 3090, 3053,
2973, 2951, 2832, 1669, 1616, 1592, 1515, 1465, 1286,
1238, 827 cm21. MS (IC): 309 (MH)þ. Anal. calcd for

A. Busch et al. / Tetrahedron 60 (2004) 5373–5382
5381
1
0 0 0
C1 ),153.1 (C8a), 148.6 (C3 ), 140.4 (C5), 135.8 (C5 ), 134.6
(40%) of 29 as a yellow solid, mp 134–135 8C; H NMR
(CDCl3): d 8.05 (d, J¼8.3 Hz, 1H, H8); 7.83 (dd, J¼8.3,
7.2 Hz, 1H, H7); 7.63 (d, J¼7.2 Hz, 1H, H6); 7.44 (d, J¼
00
(C1 ), 132.6 (C7), 130.6 (C2 , C6 ), 129.9 (C6), 128.0 (C8),
00
00
0
0
0
0
124.9 (C6 ), 122.5 (C4 ), 119.3 (C4a), 113.2 (C3 , C5 ), 55.4
(OCH3), 39.4 (Ctert-butyl), 29.8 (3£CH3tert-butyl); IR: n 3058,
3014, 2960, 2926, 2864, 2837, 1610, 1550, 1512, 1470,
1368, 1348, 1292, 1245, 1183, 1026, 827, 804, 790,
0
0
0
5.3 Hz, 1H, H2 ); 7.11 (m, 1H, H3 ); 7.02 (m, 1H, H4 ); 1.49
(s, 9H, 3£CH3tert-butyl); 13C NMR (CDCl3): d 172.3, 160.6,
152.9, 141.2, 132.6 (C7), 132.5 (C6), 132.4, 129.9 (C8),
128.9 (C4 ), 127.1 (C3 ), 126.4 (C2 ), 121.2 (C4a), 39.5
(Ctert-butyl), 29.5 (3£CH3tert-butyl); IR: n 1563, 1444, 1280,
827, 744, 712 cm21. Anal. calcd for C16H15ClN2S (302.83):
C, 63.46; N, 9.25; H, 4.99. Found: C, 63.96; N, 8.93; H,
5.09.
744 cm21 MS (EI): 369 (M)þ·. Anal. calcd for
.
0
0
0
C24H23N3O (369.47): C, 78.02; N, 11.37; H, 6.27. Found:
C, 77.69; N, 10.97; H, 6.51.
Acknowledgements
2.4.27. 2-tert-Butyl-4-(40-cyanophenyl)-5-(400-methoxy-
phenyl)quinazoline (30). Coupling of 4-cyanophenyl-
boronic acid (1.3 equiv.) with 28 (474 mg, 2 mmol)
according to the general procedure C (t¼60 h) gave after
purification by column chromatography (silica gel, eluent
petroleum ether/ethyl acetate 8/2)) 618 mg (90%) of 30 as a
yellow solid, mp 149–150 8C; 1H NMR (CDCl3): d 8.07 (d,
J¼8.3 Hz, 1H, H8); 7.89 (dd, J¼8.3, 7.2 Hz, 1H, H7); 7.53
We thank Dr. C. Andraud (ENS Lyon) for her collaboration
and the determination of the mcalcd and mb values by the
EFISH method, and L. Toupet (GMCM, CNRS 6626,
Rennes) for the X-ray diffraction study.
0
0
0
0
(d, J¼7.2 Hz, 1H, H6); 7.33 (m, 4H, H2 /3 /5 /6 ); 6.92 (d,
References and notes
00 00
00 00
J¼8.7 Hz, 2H, H2 /6 ); 6.56 (d, J¼8.7 Hz, 2H, H3 /5 ); 3.73
(s, 3H, OCH3); 1.54 (s, 9H, tert-butyl); 13C NMR (CDCl3):
1. Puglisi, J. D.; Wyatt, J. R.; Tinoco, Jr. I. Acc. Chem. Res. 1991,
24, 152.
00
d 171.8 (C2), 165.4 (C4), 159.1 (C4 ), 153.1 (C8a), 144.9
0
(C1 ), 139.9 (C5), 132.8 (C7), 131.1 (C2 , C6 ), 131.0 (C2 ,
00
00
0
2. Cozzi, F.; Siegel, J. Pure Appl. Chem. 1995, 67, 683.
3. Clough, R. L.; Roberts, J. D. J. Am. Chem. Soc. 1976, 98,
1018.
0
C6 ), 130.7 (C3 , C5 ), 130.0 (C6), 128.4 (C8), 119.2 (CN),
0
0
0
0
0
118.8 (C4a), 113.6 (C3 , C5 ), 111.5 (C4 ), 55.6 (OCH3), 39.5
(Ctert-butyl), 29.7 (3£CH3tert-butyl); IR: n 3073, 3008, 2966,
2931, 2863, 2230, 1609, 1538, 1513, 1470, 1368, 1296,
1249, 1175, 1035, 827, 812 cm21. Anal. calcd for
C26H23N3O (343.49): C, 79.36; N, 5.89; H, 10.68. Found:
C, 78.99; N, 10.33; H, 6.13.
4. House, H. O.; Campbell, W. J.; Gall, M. J. Org. Chem. 1970,
35, 1815.
5. Cozzi, F.; Ponzini, F.; Annuziata, R.; Cinquini, M.; Siegel, J. S.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1019.
6. Cozzi, F.; Cinquini, M.; Annuziata, R.; Siegel, J. S. J. Am.
Chem. Soc. 1993, 115, 5330.
2.4.28. 2-tert-Butyl-4-(40-cyanophenyl)-5-(200-thienyl)quin-
azoline (31). Coupling of 4-cyanophenylboronic acid
(1.3 equiv.) with 29 (mg, 2 mmol) according to the general
procedure C (t¼60 h) gave after purification by column
chromatography (silica gel, eluent petroleum ether/ethyl
acetate)) 221 mg (30%) of 31 as a yellow solid, mp 120–
7. Cozzi, F.; Cinquini, M.; Annuziata, R.; Dwyer, T.; Siegel, J. S.
J. Am. Chem. Soc. 1992, 114, 5729.
8. Nugent, H. M.; Rosenblum, M. J. Am. Chem. Soc. 1993, 115,
3848.
9. Cosmo, R.; Sternell, S. Aust. J. Chem. 1987, 40, 1107.
10. Komatsu, K.; Tsuji, R.; Inoue, Y.; Takeuchi, K. Tetrahedron
Lett. 1993, 34, 99.
1
121 8C; H NMR (CDCl3): d 8.09 (d, J¼8.3 Hz, 1H, H8);
7.87 (dd, J¼8.3, 7.2 Hz, 1H, H7); 7.63 (d, J¼7.2 Hz, 1H,
H6); 7.46 (d, J¼8.3 Hz, 2H, 2HPhCN); 7.39 (d, J¼8.3 Hz,
11. Kuroda, M.; Nakayama, J.; Hoshino, M.; Furusho, N.; Kawata,
T.; Ohba, S. Tetrahedron 1993, 49, 3735.
00
2H, 2HPhCN); 7.08 (d, J¼5.3 Hz, 1H, H2 ); 6.56 (m, 1H,
12. Iovine, P. M.; Kellet, M. A.; Redmore, N. P.; Therien, M. J.
J. Am. Chem. Soc. 2000, 122, 8717.
H3 ); 6.38 (m, 1H, H4 ); 1.54 (s, 9H, tert-butyl); 13C NMR
00
00
0
(CDCl3): d 172.1 (C2), 165.2 (C4), 153.1 (C8a), 145.0 (C1 ),
13. (a) Zoltewicz, J. A.; Maier, N. M.; Fabian, W. M. F. J. Org.
Chem. 1997, 62, 3215. (b) Zoltewicz, J. A.; Maier, N. M.;
Fabian, W. M. F. J. Org. Chem. 1997, 62, 2763. (c) Zoltewicz,
J. A.; Maier, N. M.; Lavieri, S.; Ghiviriga, I.; Abboud, K. A.;
Fabian, W. M. F. Tetrahedron 1997, 53, 5379. (d) Zoltewicz,
J. A.; Maier, N. M.; Fabian, W. M. F. J. Org. Chem. 1996, 61,
7018. (e) Zoltewicz, J. A.; Maier, N. M.; Fabian, W. M. F.
Tetrahedron 1996, 52, 8703. (f) Zoltewicz, J. A.; Maier, N. M.;
Fabian, W. M. F. J. Org. Chem. 1998, 63, 4985. (g) Lavieri, S.;
Zoltewicz, J. A. J. Org. Chem. 2001, 66, 7227.
14. (a) Bahl, A.; Grahn, W.; Stadler, S.; Feiner, F.; Bourhill, G.;
00
142.0 (C1 ), 132.7 (C5), 132.4 (C7), 131.2 (2£CHPhCN),
00
131.0 (C6), 130.0 (2£CHPhCN), 129.7 (C4 ), 129.4 (C8),
00
00
127.5 (C3 ), 126.4 (C2 ), 119.7 (CN), 119.0 (C4a), 111.9
00
(C2 ), 39.6 (Ctert-butyl), 29.8 (3£CH3tert-butyl). HRMS(IC)
calculated for C23H20N3S: 370.1378. Found: 370.1380.
2.4.29. 2-tert-Butyl-5-(400-methoxyphenyl)-4-(20-pyridyl)-
quinazoline (32). Coupling of (2-pyridyl)-tributylstannane
(1.3 equiv.) with 28 (474 mg, 2 mmol) according to the
general procedure D (t¼48 h) gave after purification by
column chromatography (silica gel, eluent: petroleum ether/
ethyl acetate 8/2) 236 mg (32%) of 32 as a yellow solid, mp
¨
Brauchle, C.; Reisner, A.; Jones, P. G. Angew. Chem. Int., Ed.
Engl. 1995, 34, 1485. (b) Di Bella, S.; Fragala, L.; Ratner,
M. A.; Marks, T. J. J. Am. Chem. Soc. 1993, 115, 682.
15. Hunter, C. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 1584.
16. Warrener, R. N.; Russell, R. A.; Marcuccio, S. M. Aust.
J. Chem. 1980, 33, 2777.
1
107–108 8C; H NMR (CDCl3): d 8.11 (d, J¼4.9 Hz, 1H,
0
H3 ); 8.05 (d, J¼8.3 Hz, 1H, H8); 7.86 (dd, J¼8.3, 7.5 Hz,
0
0
1H, H7); 7.66 (d, J¼7.9 Hz, 1H, H6 ); 7.53 (m, 2H, H6/5 );
00 00
0
00 00
6.95 (m, 3H, H2 /6 /4 ); 6.54 (d, J¼8.3 Hz, 2H, H3 /5 ); 3.72
(s, 3H, OCH3); 1.56 (s, 9H, tert-butyl); 13C NMR (CDCl3):
17. (a) Jones, P. G.; Grahn, W.; Bahl, A.; Reisner, A.
Z. Kristallogr. 1995, 210, 229. (b) Clough, R. L.; Kung,
00
0
d 171.6 (C2), 165.8 (C4), 158.4 (C4 or C1 ), 158.3 (C4 or
00

5382
A. Busch et al. / Tetrahedron 60 (2004) 5373–5382
W. J.; Marsh, R. E.; Roberts, J. D. J. Org. Chem. 1976, 41,
3603.
18. Gautheron-Chapoulaud, V.; Salliot, I.; Ple, N.; Turck, A.;
´
Queguiner, G. Tetrahedron 1999, 55, 5389.
19. Sugimoto, O.; Yamauchi, Y.; Tanji, K. I. Heterocycles 2002,
57, 323.
23. (a) Murray, T. P.; Hay, J. V.; Portlock, D. E.; Wolfe, J. F.
J. Org. Chem. 1974, 39, 595. (b) Rathman, T. L.; Sleevi, M. C.;
Krafft, M. K.; Wolfe, J. F. J. Org. Chem. 1980, 45, 2169.
24. (a) Srinivasan, A.; Broom, A. D. J. Org. Chem. 1979, 44, 435.
(b) Anderson, G. L.; Shim, J. L.; Broom, A. D. J. Org. Chem.
1977, 42, 993. (c) Oakes, V.; Rydon, H. N. J. Chem. Soc. 1956,
4433. (d) Oakes, V.; Rydon, H. N.; Undheim, K. J. Chem. Soc.
1962, 4678. (e) Oakes, V.; Rydon, H. N. U.S. Patent No 2,924,
599, 1960; Chem. Abstr. 1960, 54, 9964..
´
´ ´
20. Ple, N.; Turck, A.; Chapoulaud, V.; Queguiner, G.
Tetrahedron 1997, 53, 2871.
21. Connoly, D. J.; Guiry, P. J. Synlett 2001, 11, 1707.
22. Armarego, W. L. F. Fused Pyrimidines, Part 1, Quinazolines00,
Chemistry of Heterocyclic Compounds; Wiley: New York,
1967.
25. Coulson, D. R. Inorg. Synth. 1972, 18, 121.